Download Molecular Pathways: Fatty Acid Synthase

Published OnlineFirst October 30, 2015; DOI: 10.1158/1078-0432.CCR-15-0126
Clinical
Cancer
Research
Molecular Pathways
Molecular Pathways: Fatty Acid Synthase
Suzanne F. Jones and Jeffrey R. Infante
Abstract
Therapies that target tumor metabolism represent a new horizon in anticancer therapies. In particular, cancer cells are dependent on the generation of lipids, which are essential for cell
membrane synthesis, modification of proteins, and localization
of many oncogenic signal transduction enzymes. Because fatty
acids are the building blocks of these important lipids, fatty acid
synthase (FASN) emerges as a unique oncologic target. FASN
inhibitors are being studied preclinically and beginning to tran-
sition to first-in-human trials. Early generation FASN inhibitors
have been studied preclinically but were limited by their pharmacologic properties and side-effect profiles. A new generation of
molecules, including GSK2194069, JNJ-54302833, IPI-9119, and
TVB-2640, are in development, but only TVB-2640 has moved
into the clinic. FASN inhibition, either alone or in combination,
holds promise as a novel therapeutic approach for patients with
cancer. Clin Cancer Res; 21(24); 5434–8. 2015 AACR.
Background
The biologic role and physiology of fatty acid synthase
Fatty acids are critical for energy metabolism and are the fundamental components of all cell membrane lipids (1). Interestingly, de novo biosynthesis is not the main way adult mammalian
tissues fulfill their lipid needs. Free fatty acids (FFA) and lipoproteins are more commonly obtained from the diet via the blood
circulation. Interestingly, germline knockout (KO) of Fasn is not
tolerated with embryos dying preimplantation. Even haploidy,
Fasnþ/–, miceexperience a 70% loss of embryos and cannot support
embryonic development (5). However, in later development most
adult tissues have very little Fasn expressed, with the notable
exceptions of lactating breast and cycling endometrium (6, 7).
Many adult mouse models show that Fasn can often be deleted
from many tissues under normal conditions without significant
consequence or sequalae. For instance, mice with a liver-specific
KO of Fasn have only a mild decrease in cholesterol and liver
palmitate and a 2-fold increase in liver malonyl-CoA (8). This
likely explains why there is minimal phenotypic change from their
wild-type counterparts when fed a regular diet. Conversely, if fed a
zero-fat diet, then these KO liver mice develop hyperglycemia and,
paradoxically, steatosis. Finally, these observed defects can be
overcome by restoring normal diet or adding a PPARa agonist.
Introduction to lipid metabolism as a target in cancer
It has been long recognized that cancer cells rely heavily on
aerobic glycolysis to fuel the high rate of DNA and protein
synthesis needed for malignant cell growth, replication, and
proliferation (1). Years ago, it was also demonstrated that tumor
tissues require a surge in lipid metabolism to accommodate the
increased requirement for synthesis of membranes, energy storage, and signaling functions (2, 3). Fatty acids are the major
components of these highly important lipids and fatty acid
synthase (FASN) is the lone lipogenic enzyme in humans able
to synthesize these all important fatty acids de novo. Herein, we
describe the potential therapeutic implications of inhibiting FASN
in cancer patients.
Fatty acid synthase: an integrated target in tumor cell biology
As cancer cells fervently consume glucose, pyruvate is made via
the glycolytic pathway. Pyruvate is subsequently fed into the Krebs
cycle in the mitochondria to yield ATP (4). One of the by-products
of this reaction is acetyl-coenzyme A (CoA); it together with
malonyl-CoA becomes the substrates for FASN, which catalyzes
the biosynthesis of the fatty acid palmitate in a nicotinamide
adenine dinucleotide phosphate–reduced (NADPH)-dependent
reaction. Palmitate can then either be conjugated to other proteins
or converted to other fatty acids and complex lipids that are vital
for (i) lipid synthesis and membrane structures, such as lipid rafts,
(ii) protein modification and localization functions, and (iii)
receptor localization and signaling of major oncogenic pathways
such as the PI3K/AKT/mTOR pathway (Fig. 1).
Sarah Cannon Research Institute, Nashville, Tennessee.
Corresponding Author: Jeffrey R. Infante, Sarah Cannon Research Institute/
Tennessee Oncology, PLLC, 250 25th Avenue North, Suite 200, Nashville, TN
37203. Phone: 6153297423; Fax: 6153297558; E-mail: [email protected]
doi: 10.1158/1078-0432.CCR-15-0126
2015 American Association for Cancer Research.
FASN and cancer
The first association of FASN expression with a malignancy was
identified in breast cancer tumors in 1994, formerly described as
the antigen OA-519 (9). Since that initial observation, overexpression of FASN has been detected in multiple tumor types, including
pancreas, colorectal, ovarian, breast, and prostate cancer (10–15).
Interestingly, in many of these reports higher levels of FASN
correlate with increasing tumor burden, later stages of disease,
and poor prognosis.
A few studies have tried to establish that forcing the expression
of Fasn above normal levels can drive a malignant phenotype. In
one example, in vitro ectopic overexpression of Fasn in breast
cancer cells was shown to enhance lipogenesis along with
increased cell growth and proliferation (16). Transgenic expression of Fasn in mice showed a significant increase in prostate
epithelial neoplasia but this alone was not sufficient enough to
result in invasive tumors. Further studies with immortalized
5434 Clin Cancer Res; 21(24) December 15, 2015
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Published OnlineFirst October 30, 2015; DOI: 10.1158/1078-0432.CCR-15-0126
FASN
Acetyl-CoA
Malonyl-CoA
FASN
Figure 1.
FASN—integrated target in tumor cell
biology. FASN catalyzes the synthesis
of palmitate from acetyl-CoA and
malonyl-CoA. Palmitate is then
converted to other fatty acids/
complex lipids critical for lipid
synthesis and membrane structures,
protein modification and localization
functions, and receptor localization
and signaling of major oncogenic
signaling pathways.
FASN inhibitor
Palmitate
Lipid
rafts
b-catenin
P
Lipid synthesis
and membrane
structure
Protein
modification
and localization/
function
Receptor
localization and
signaling of major
oncogenic pathways
WNT
PI3K
APC
Axin
mTOR
P
AKT
GSK3
Dvl
LRP
pS6
RTK
Frizzled
WNT
© 2015 American Association for Cancer Research
prostate epithelial cells (iPrEC) suggested that in addition to the
Fasn expression, coexpression of androgen receptor was required
for invasive adenocarcinoma (17). Though these studies do not
establish FASN as a true oncogene, one can see the unique
association between FASN expression and neoplasia.
Clinical–Translational Advances
Multiple FASN inhibitors are in development and under
preclinical evaluation. Unfortunately, there are some limitations to interpreting the effects of FASN inhibition in the
different disease models as the early generation of FASN inhibitors, such as cerulenin, C-75, and orlistat, are limited by
significant off-target toxicity and tissue distribution. The majority of the evidence suggests FASN inhibition results in cancer
cell death by multiple mechanisms, including altering membrane synthesis, protein modification, and interactions with
other oncogenic signaling pathways.
Multiple studies support a primary mechanism of action associated with FASN inhibition to be a disruption in membrane
synthesis. The current selective molecules in development allosterically inhibit the b-ketoacyl reductase activity of FASN. By
www.aacrjournals.org
blocking the enzymatic activity of FASN, cellular malonyl-CoA
increases with a concomitant decrease in phospholipid production. In vitro these changes inhibit proliferation of cancer cell lines
and alter both metabolic pathway metabolites and mRNA expression of metabolic genes (18). Both cerulenin and C-75 have been
studied in liposarcoma models in vitro, and as expected the effects
could be overcome by the addition of palmitate. siRNA specific for
FASN in addition to C-75 resulted in tumor growth regression of
70% and 80%, respectively, in prostate xenograft models as
compared with control (19). This tumor growth reduction was
associated with a corresponding decrease in FASN expression
evaluated by Western blot at the end of treatment (P < 0.05).
Similarly RNAi expressing plasmids that inhibited FASNdecreased osteosarcoma cell invasion and metastasis in vitro (20).
In addition to disrupting lipid membrane synthesis, FASN
inhibition can also affect modification of proteins by palmitoylation. This has been most well examined with the Wnt/b-catenin
pathway. In one study of 862 cases of human prostate cancer,
overexpression of FASN correlated with WNT-1 palmitoylation
and stabilization of b-catenin (P < 0.001; ref. 21). The palmitate
moiety on Wnt is critical for appropriate secretion from the cell
and its ability to transduce activation signals to b-catenin
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5435
Published OnlineFirst October 30, 2015; DOI: 10.1158/1078-0432.CCR-15-0126
Jones and Infante
following binding to its cognate receptor. FASN inhibition not
only can reduce this important posttranslation modification of
these proteins, but also may have more specific effects on the
activation of b-catenin alone. By disrupting the classical Wnt/
b-catenin pathway, expression of important tumor survival proteins such as c-MYC can be significantly reduced (22).
As a third potential anticancer mechanism, FASN is known to
regulate and integrate with other oncogenic signaling pathways,
including protein kinase C (PKC), HER2, and the PI3K/AKT/
mTOR pathways. In a recent study, investigators used lipidomic
analyses to show that in certain tumor cell lines, the inhibition of
FASN led to a reduction of specific diacylglycerols (DAG; ref. 23).
As DAGs normally stimulate PKC; by reducing their levels, the
activity of PKC was reduced ultimately leading to apoptosis of the
cells. Conversely, in tumor cells that did not undergo apoptosis in
response to FASN inhibition, there was no concomitant reduction
in DAGs.
FASN has also been shown to stimulate the activity of HER2
receptor, possibly as a result of enabling assembly of multiprotein signaling complexes at discrete portions of the cellular
membrane such as lipid rafts. Either through stimulation of a
cellular receptor, such as HER2, or other mechanisms, FASN often
increases signaling through the PI3K/AKT/mTOR axis. This
becomes a self-amplifying pathway, increasing mTOR activity
which in turn increases activity of the transcription factor
SREBP-1, leading to an increase in FASN mRNA expression (24).
FASN inhibition in patients
Multiple FASN inhibitors, such as cerulenin, orlistat, C75, C93,
and GSK837149A, have demonstrated preclinical antitumor
activity in cancer cell lines and xenograft models (4, 25). None
of these compounds have been tested in cancer patients due to
limitations imparted by their pharmacologic properties or sideeffect profiles that would limit their clinical development. A new
generation of molecules such as GSK2194069 (26), JNJ54302833 (27), IPI-9119 (28), and TVB-2640 (29) are in development, but only TVB-2640 has moved into the clinic.
TVB-2640 is the first oral, selective, potent, reversible FASN
inhibitor tested clinically. Preliminary results from the first-inman dose escalation trial demonstrated on-target, reversible skin
(including peeling and palmar-plantar erythrodysesthesia) and
ophthalmologic (including corneal edema, keratitis, and iritis)
toxicities at the highest continuous oral doses administered (29).
Pharmacodynamic biomarkers, such as increased serum concentrations of malonyl carnitine and decreased serum concentrations
of TG 16:0 palmitate, indicate target engagement following TVB2640 dosing (30). In this early, first-in-human trial prolonged
stable disease has been seen with monotherapy. In addition, when
TVB-2640 was given in combination with paclitaxel, a confirmed
PR was observed in a patient with peritoneal serous carcinoma as
well as prolonged stable disease in both non–small cell lung
carcinoma (NSCLC) and breast cancer patients (31).
Future directions
Since the first FASN inhibitors just entered the clinic, there is a
paucity of data to support proof of mechanism within tumor cells
of patients. Novel biomarker strategies to assess level of FASN
inhibition, cell signaling changes, and lipid proteomic alterations
will be critical to accelerate the development of this class of drugs.
Furthermore, studies enabling a clear patient selection strategy are
at the earliest stages of discovery at this time. Without a genomic
5436 Clin Cancer Res; 21(24) December 15, 2015
mutation or tumor-specific fusion protein driving the oncogenic
properties inherent to FASN overexpression, as observed with
BRAF, ALK, and EGFR (32–34), it remains a challenge to identify
and match the best patients to these novel inhibitors. Alternatively, tumor heterogeneity, which remains the Achilles heel of the
precision medicine era, may be less of an issue with metabolic
agents that broadly affect lipid production.
Although efforts remain ongoing to identify the best monotherapy strategy, there is good rationale supporting a combination
development strategy. FASN inhibition accentuates the activity of
multiple different cytotoxic chemotherapies, particularly taxanes.
Both docetaxel and paclitaxel synergize with FASN inhibitors
in vitro (35, 36). In addition, a potent synergistic relationship
with a combination of paclitaxel and a FASN inhibitor has been
demonstrated in xenograft models of NSCLC as well as other
tumor types (37). Indeed, the clinical trial of TVB-2640 (ClinicalTrials.gov: NCT02223247) is currently enrolling paclitaxel
combination cohorts (29). Furthermore, the addition of a FASN
inhibitor was able to restore sensitivity in a number of tumor
models in which the cells had become resistant to another
chemotherapeutic agent. FASN inhibition can resensitize in vitro
hepatocellular carcinoma cells known to be taxane resistant (38).
Similar results were obtained for cells that had become resistant to
doxorubicin (39). These investigators demonstrated that a FASN
inhibitor altered the lipid composition of the plasma membrane
of these cells allowing doxorubicin to more easily traverse the
membrane and regain its antitumor activity (25, 22). Blockade of
FASN can also reverse resistance to trastuzumab and lapatinib in
HER2-resistant cell lines (4, 40).
In summary, therapies that target tumor metabolism represent
a new horizon in anticancer therapies. FASN inhibition represents
one of the first strategies in this area, though other metabolism
targets, including isocitrate dehydrogenase, glutaminase, and
argininase, are already either being tested in patients or making
their way toward the clinic (41–44). FASN is uniquely associated
with cancer, and preclinical data provide evidence of antitumor
activity. The identification of biomarkers to support proof of
mechanism and potentially aid in patient selection remains an
active area of investigation. FASN inhibition, either alone or in
combination, holds promise as a novel therapeutic approach for
patients with cancer.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: J.R. Infante
Development of methodology: J.R. Infante
Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): J.R. Infante
Analysis and interpretation of data (e.g., statistical analysis, biostatistics,
computational analysis): J.R. Infante
Writing, review, and/or revision of the manuscript: S.F. Jones, J.R. Infante
Administrative, technical, or material support (i.e., reporting or organizing
data, constructing databases): J.R. Infante
Acknowledgments
The authors thank George Kemble, PhD, and Merdad Parsey, MD, PhD, for
help with the writing of this article. They also thank Laura DeBusk, PhD, for
formatting and editing the article.
Received July 17, 2015; revised September 11, 2015; accepted October 15,
2015; published OnlineFirst October 30, 2015.
Clinical Cancer Research
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Published OnlineFirst October 30, 2015; DOI: 10.1158/1078-0432.CCR-15-0126
FASN
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Clinical Cancer Research
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Published OnlineFirst October 30, 2015; DOI: 10.1158/1078-0432.CCR-15-0126
Molecular Pathways: Fatty Acid Synthase
Suzanne F. Jones and Jeffrey R. Infante
Clin Cancer Res 2015;21:5434-5438. Published OnlineFirst October 30, 2015.
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